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Cambridge Cardiovascular

Functional genomics: Shedding light on cardiovascular disease

Dr Mattia Frontini has previously been supported by the BHF Cambridge Centre of Research Excellence as a non-clinical Career Development Fellow. The BHF has recently awarded him his first Senior Research Fellowship (£900K, 2019-2024).

A disease’s predisposition has often been regarded as genetic, yet the quest to seek out ‘the disease gene’ has frequently met a dead end.

Dr Mattia Frontini has taken a different approach that appears to be leading to fruition. He uses functional genomics to bridge the gap between a person's genetic make-up and phenotype (disease) exhibited to also consider environmental exposures. As opposed to focusing on sequence variations in DNA, functional genomics uses a dynamic approach, investigating the interplay between environment and genome. This interplay is also known as epigenetic.

The integration of environmental cues leads to changes in gene expression and protein–protein interactions that ultimately influence the phenotype at organism and cellular level. Historically, vast expanses of the genome were considered irrelevant and devoid of any function. However, it has been now recognised that these regions play a very important role in controlling gene expression. Dr Frontini investigates these regulatory regions to see how they influence the activity of genes in blood traits and disorders.

“Some regions can sit in the middle of nowhere in the genome, which makes us think: which gene does this region interact with?” he explains.

In collaboration with Prof Peter Fraser and Dr Mikhail Spivakov (then at the Babraham institute - now at Florida State University (USA) and MRC London Institute of Medical Sciences, respectively), Dr Frontini has investigated how the genome folds and how this influences the interaction of the promoters of genes with regulatory elements – with a technique known as promoter capture (HiC).

Using these approaches, Dr Frontini and colleagues have identified the regulatory landscape of 20,000 genes in 17 primary blood cell types - thus identifying the potential causal gene of thousands of disease linked genetic variants. Moreover, using the same approach he has shown that genetic variations that influence platelet count and volume, modifies the way platelet behave during thrombus formation by modulating the expression of the genes they regulate.

Additionally, Dr Frontini has been part of the BluePrint consortium, an EU-funded project whereby blood cells from healthy patients were isolated and characterised to further our understanding of epigenetic changes that influence gene expression and phenotypic traits.

In 2015, Dr Frontini was awarded a Career Development Fellowship by the BHF Cambridge Centre of Research Excellence to investigate the interplay between chronic inflammation and myeloid cells production.

“This is very interesting as myeloid cells exposed to chronic inflammation can modify their phenotypes and this can be part of the increased risk for cardiovascular disease” he explains.

Dr Frontini's research team is looking at the epigenetics of myeloid cells taken from healthy blood donors, patients with lipodystrophies and obese patients before and after bariatric surgery to identify differences in gene expression programs and epigenetic signatures.

“We may find that myeloid cells from patients exposed to chronic inflammation may provide early markers of cardiovascular disease development such as altered levels of lipids and other metabolites in their blood” he states.

This exciting research shines the spotlight firmly on epigenetics and how these changes, rather than changes to DNA sequence, have a far greater influence on a phenotype than previously thought. Additionally, the framework can be used to pinpoint the genes responsible for rare inherited diseases, for which it is notoriously difficult to identify causative mutation. A functional genomic approach will allow to determine a genetic diagnosis and potentially provide therapeutic targets for more targeted therapies. The quest for disease genes, it seems, is now an open road to discovery.

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